At the first presidential nominating convention of the Libertarian Party in 1972, Nathan was nominated by the convention delegates to run for vice president with presidential candidate John Hospers, chairman of the philosophy department at the University of Southern California. While the ticket received only 3,674 official votes out of more than 75 million votes cast,[5] Republican elector Roger MacBride of Virginia chose to vote for Hospers and Nathan instead of Nixon and Agnew. As a result, Nathan became the first woman and the first Jew in American history to have received an electoral vote in a presidential election.[1][6] Nathan and Hospers campaigned on a platform of minimal government intervention.[7]

Nathan consented to have her name put forward for the Libertarian vice-presidential nomination in the 1976 presidential election, though she did not actively campaign for the position.[8] She lost that nomination to Jim Lewis.

Nathan was a founding member and former vice chair of the Libertarian Party,[4][8] as well as a founding member and former president of the Association of Libertarian Feminists.[13] She was a speaker at the 2012 Libertarian National Convention, where she also announced Gary Johnson as the 2012 Libertarian Party presidential nominee.[14]

Nathan was originally a Democrat until one of her sons, Paul, gave her some writings by Ayn Rand. That helped spur his mother’s political views of freedom, free markets and individuality, and prompted her to switch her political allegiance from the Democratic to Libertarian Party, Paul said, and attended the party's first national convention in 1972 in Colorado as an interested observer and freelance writer until she was ultimately asked to join the party's national ticket as a running mate. Throughout the years, Nathan championed a number of social and fiscal issues such as ending the military draft and the war on drugs, advocating historic preservation, abortion rights and a flat tax.[15]

During the 2004 presidential election, Nathan wrote a column for LewRockwell.com saying that Americans "should vote their consciences and pick the candidate who best represents their values." She also stated, "It makes you wonder, doesn't it. What is the major news media afraid of? Could it be that most Americans share the Libertarian ideals of Republican fiscal conservatism (reducing the size and cost of government) and Democratic social liberalism (allowing citizens control over their personal lives)? Perhaps such Libertarian views represent a genuine threat to both major parties…" and "It is possible that during the coming debates President Bush or Senator Kerry will discuss the many issues that created reasons for new political parties to form — issues on environmentalism, a possible draft, the Drug War, abortion and gay rights, the falling dollar, immigration laws, foreign policy principles, the unwieldy IRS code and the Supreme Court's adherence to the Constitution."[16]